Prophylactic and/or therapeutic agent containing pyridylaminoacetic acid compound

ABSTRACT

The object of the present invention is to find a new application of isopropyl (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate or a salt thereof. Isopropyl (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate or a salt thereof is useful as a therapeutic agent for a disease involving a greatly elevated intraocular pressure.

TECHNICAL FIELD

The present invention relates to a prophylactic and/or therapeutic agentcontaining isopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetateor a salt thereof.

BACKGROUND ART

Glaucoma is an eye disease in which an elevated intraocular pressure dueto various causes may damage the tissues (retina, optic nerve, and thelike) inside the eyeball and lead to visual loss. In general,intraocular pressure-lowering therapies have been employed as treatmentmethods for glaucoma, and representative intraocular pressure-loweringtherapies include drug therapies, laser therapies, surgical therapies,and the like.

Here, for treating some types of glaucoma, for example, primary angleclosure glaucoma, a treatment of rapidly lowering the greatly elevatedintraocular pressure has been conducted by intravenous administration,oral administration, or the like of acetazolamide before radicaltreatment such as iridotomy. However, it cannot be said that thistreatment is sufficient in terms of safety and efficacy, and there hasbeen a demand for a new drug therapy which is safer, and which lowersthe greatly elevated intraocular pressure more rapidly.

Isopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetateis a compound represented by the following formula (1) and described inPatent Literature 1 as one of the numerous pyridylaminoacetic acidcompounds:

In addition, it is stated that these pyridylaminoacetic acid compoundshave EP2 agonist action (Patent Literature 2), and are expected to haveintraocular pressure-lowering activity, and may be used as a therapeuticagent for glaucoma (Patent Literature 1).

Moreover, Patent Literatures 3 and 4 state that a combination of thecompound represented by the above-described formula (1) with anothertherapeutic agent for glaucoma such as timolol increases the intraocularpressure-lowering activity. Note that the entire contents described inPatent Literatures 1 to 4 are incorporated herein by reference.

However, there has been no report on the point that the compoundrepresented by the above-described formula (1) or a salt thereof canlower a greatly elevated intraocular pressure rapidly and safely.

CITATION LIST Patent Literature

-   [Patent Literature 1] United States Patent Application Publication    No. 2012/0190852-   [Patent Literature 2] United States Patent Application Publication    No. 2011/0054172-   [Patent Literature 3] United States Patent Application Publication    No. 2014/0018396-   [Patent Literature 4] United States Patent Application Publication    No. 2014/0018350

SUMMARY OF INVENTION

An object of the present invention is to find a new medicinal use of theabove-described compound represented by the formula (1) or a saltthereof.

To achieve the above-described object, the present inventors haveconducted intensive studies, and found that isopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetateor a salt thereof (hereinafter, also referred to as “the presentcompound”) lowers a greatly elevated intraocular pressure safely andrapidly. This finding has led to the completion of the presentinvention.

Specifically, the present invention relates to the following.

[1] A prophylactic and/or therapeutic agent for a disease involving agreatly elevated intraocular pressure, comprising isopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetateor a salt thereof.[2] The prophylactic and/or therapeutic agent according to theabove-described item [1], wherein

the disease involving a greatly elevated intraocular pressure is acuteprimary angle closure, primary angle closure glaucoma, secondary angleclosure glaucoma, or acute intraocular pressure elevation.

[3] The prophylactic and/or therapeutic agent according to theabove-described item [1] or [2], comprising 0.001 to 0.03% (w/v) of theisopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetateor the salt thereof.[4] The prophylactic and/or therapeutic agent according to anyone of theabove-described items [1] to [3], which does not comprise any otherprophylactic and/or therapeutic agent for glaucoma or ocularhypertension than isopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetateor a salt thereof.[5] An eye drop, comprising the prophylactic and/or therapeutic agentaccording to any one of the above-described items [1] to [4].[6] Isopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetateor a salt thereof for the use of preventing and/or treating a diseaseinvolving a greatly elevated intraocular pressure.[7] Isopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetateor a salt thereof according to the above-described item [6], wherein thedisease involving a greatly elevated intraocular pressure is acuteprimary angle closure, primary angle closure glaucoma, secondary angleclosure glaucoma, or acute intraocular pressure elevation.[8] An eye drop, comprising isopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetateor a salt thereof according to the above-described item [6] or [7].[9] Use of isopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetateor a salt thereof for preparing a prophylactic and/or therapeutic agentfor a disease involving a greatly elevated intraocular pressure.[10] The use according to the above-described item [9], wherein thedisease involving a greatly elevated intraocular pressure is acuteprimary angle closure, primary angle closure glaucoma, secondary angleclosure glaucoma, or acute intraocular pressure elevation.[11] The use according to the above-described item [9] or [10],comprising 0.001 to 0.03% (w/v) of the isopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetateor the salt thereof.[12] The use according to any one of the above-described items [9] to[11], which does not use any other prophylactic and/or therapeutic agentfor glaucoma or ocular hypertension than isopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetateor a salt thereof.[13] The use according to anyone of the above-described items [9] to[12], wherein the prophylactic and/or therapeutic agent is an eye drop.[14] A method for preventing and/or treating a disease involving agreatly elevated intraocular pressure, comprising administeringisopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetateor a salt thereof to patients with said disease which has to beprevented and/or treated.[15] The method according to the above-described item [14], wherein thedisease involving a greatly elevated intraocular pressure is acuteprimary angle closure, primary angle closure glaucoma, secondary angleclosure glaucoma, or acute intraocular pressure elevation.[16] The method according to the above-described item [14] or [15],wherein the administration amount of the isopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetateor the salt thereof is 0.001 to 0.03% (w/v).[17] The method according to any one of the above-described items [14]to [16], wherein any other prophylactic and/or therapeutic agent forglaucoma or ocular hypertension than isopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetateor a salt thereof is not administered.[18] The method according to any one of the above-described items [14]to [17], wherein the administration is instillation.

Note that it is possible to combine any two or more selected from theabove-described configurations [1] to [5]. It is possible to combine anytwo or more selected from the above-described configurations [6] to [8],and the explanations regarding “prophylactic and/or therapeutic agent”in this specification may also be applied to these embodiments regardingsaid “isopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetateor a salt thereof.” It is also possible to combine any two or moreselected from the above-described configurations [9] to [13], and theexplanations regarding “prophylactic and/or therapeutic agent” in thisspecification may also be applied to these embodiments regarding said“use.” It is also possible to combine any two or more selected from theabove-described configurations [14] to [18], and the explanationsregarding “prophylactic and/or therapeutic agent” in this specificationmay also be applied to these embodiments regarding said “method.”

DESCRIPTION OF EMBODIMENTS

Hereinafter, embodiments of the present invention are described indetail. Note that, in the following description, the “prophylacticand/or therapeutic agent” of the present invention is simply referred toas “therapeutic agent”, unless otherwise noted.

Isopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetateor a salt thereof contained in the therapeutic agent of the presentinvention can be produced according to the method described in UnitedStates Patent Application Publication No. 2012/0190852 (PatentLiterature 1), an ordinary method in the technical field, or the like.

The salt of isopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetatecontained in the therapeutic agent of the present invention is notparticularly limited, as long as the salt is pharmacologicallyacceptable. Specifically, the salt may be an inorganic acid salt such ashydrochloric acid salt, hydrobromic acid salt, hydroiodic acid salt,nitric acid salt, sulfuric acid salt, or phosphoric acid salt; anorganic acid salt such as acetic acid salt, trifluoroacetic acid salt,benzoic acid salt, oxalic acid salt, malonic acid salt, succinic acidsalt, maleic acid salt, fumaric acid salt, tartaric acid salt, citricacid salt, methanesulfonic acid salt, ethanesulfonic acid salt,trifluoromethanesulfonic acid salt, benzenesulfonic acid salt,p-toluenesulfonic acid salt, glutamic acid sal, or aspartic acid salt;or the like. The salt is preferably a hydrochloric acid salt or atrifluoroacetic acid salt.

The content of isopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetateor the salt thereof in the therapeutic agent of the present invention isnot particularly limited. In the case of an eye drop, the lower limit ofthe content is preferably 0.0003% (w/v), more preferably 0.001 (w/v),further preferably 0.0013% (w/v), and particularly preferably 0.0015%(w/v). Meanwhile, the upper limit of the content is preferably 0.03%(w/v), more preferably 0.01% (w/v), further preferably 0.005% (w/v),particularly preferably 0.003% (w/v), and especially preferably 0.0027%(w/v). More specifically, the content is preferably 0.0003 to 0.03%(w/v), more preferably 0.001 to 0.01% (w/v), further preferably 0.001 to0.005% (w/v), particularly preferably 0.001 to 0.003% (w/v), especiallypreferably 0.0013 to 0.003% (w/v), and still further preferably 0.0015to 0.0027% (w/v). More specifically, the content is preferably 0.0010%(w/v), 0.0011% (w/v), 0.0012% (w/v), 0.0013% (w/v), 0.0014% (w/v),0.0015% (w/v), 0.0016% (w/v), 0.0017% (w/v), 0.0018% (w/v), 0.0019%(w/v), 0.0020% (w/v), 0.0021% (w/v), 0.0022% (w/v), 0.0023% (w/v),0.0024% (w/v), 0.0025% (w/v), 0.0026% (w/v), 0.0027% (w/v), 0.0028%(w/v), 0.0029% (w/v), 0.0030% (w/v), 0.005% (w/v), 0.01% (w/v), or 0.03%(w/v), or the content is preferably in a range having an upper limit ora lower limit selected from any of these amounts. Here, the term “%(w/v)” means the mass (g) of an active ingredient (the present compoundhere) or an additive (surfactant or the like) contained per 100 mL ofthe eye drop. For example, 0.01% (w/v) of the present compound meansthat the content of the present compound per 100 mL of the eye drop is0.01 g.

Note that, when a salt of isopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetateis contained, this content means that the content of isopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate,which is the free form of the salt, is within the above-described range.

If necessary, additives can be used in the therapeutic agent of thepresent invention. As the additives, for example, a surfactant, abuffering agent, a tonicity adjusting agent, a stabilizer, an antisepticagent, an antioxidant, a high-molecular weight polymer, and the like canbe added.

In the therapeutic agent of the present invention, a surfactant usableas an additive for pharmaceuticals can be blended, as appropriate.

Examples of the surfactant include polyoxyethylene castor oils,polyoxyethylene hardened castor oils, polyoxyethylene sorbitan fattyacid esters, vitamin E TPGS, polyoxyethylene fatty acid esters,polyoxyethylene polyoxypropylene glycols, sucrose fatty acid esters, andthe like.

More specifically, as the polyoxyethylene castor oils, variouspolyoxyethylene castor oils having different degrees of polymerizationof ethylene oxide can be used. The degree of polymerization of ethyleneoxide is preferably 5 to 100, more preferably 20 to 50, particularlypreferably 30 to 40, and most preferably 35. Specific examples of thepolyoxyethylene castor oils include polyoxyl 5 castor oil, polyoxyl 9castor oil, polyoxyl 15 castor oil, polyoxyl 35 castor oil, polyoxyl 40castor oil, and the like, and polyoxyl 35 castor oil is the mostpreferable.

As the polyoxyethylene hardened castor oils, various polyoxyethylenehardened castor oils having different degrees of polymerization ofethylene oxide can be used. The degree of polymerization of ethyleneoxide is preferably 10 to 100, more preferably 20 to 80, particularlypreferably 40 to 70, and most preferably 60. Specific examples of thepolyoxyethylene hardened castor oils include polyoxyethylene hardenedcastor oil 10, polyoxyethylene hardened castor oil 40, polyoxyethylenehardened castor oil 50, polyoxyethylene hardened castor oil 60, and thelike, and polyoxyethylene hardened castor oil 60 is the most preferable.

The polyoxyethylene sorbitan fatty acid esters include polysorbate 80,polysorbate 60, polysorbate 40, polyoxyethylene sorbitan monolaurate,polyoxyethylene sorbitan trioleate, polysorbate 65, and the like, andpolysorbate 80 is the most preferable.

Vitamin E TPGS is also referred to as tocopherol polyethylene glycol1000 succinate.

The polyoxyethylene fatty acid esters include polyoxyl 40 stearate, andthe like.

The polyoxyethylene polyoxypropylene glycols include polyoxyethylene(160) polyoxypropylene (30) glycol, polyoxyethylene (42)polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39)glycol, polyoxyethylene (196) polyoxypropylene (67) glycol,polyoxyethylene (20) polyoxypropylene (20) glycol, and the like.

The sucrose fatty acid esters include sucrose stearate and the like.

When a surfactant is blended in the therapeutic agent of the presentinvention, the content of the surfactant can be adjusted, asappropriate, according to the type of the surfactant and the like.Specifically, the lower limit is preferably 0.001% (w/v), morepreferably 0.01% (w/v), further preferably 0.1% (w/v), particularlypreferably 0.5% (w/v), and most preferably 0.8% (w/v). The upper limitis preferably 10% (w/v), more preferably 5% (w/v), further preferably 4%(w/v), particularly preferably 3% (w/v)), and most preferably 2% (w/v).More specifically, the content is preferably 0.001 to 10% (w/v), morepreferably 0.01 to 5% (w/v), further preferably 0.1 to 4% (w/v),particularly preferably 0.5 to 3% (w/v), and most preferably 0.8 to 2%(w/v).

In the therapeutic agent of the present invention, a buffering agentusable as an additive for pharmaceuticals can be blended, asappropriate.

Examples of the buffering agent include phosphoric acid, salts thereof,boric acid, salts thereof, citric acid, salts thereof, acetic acid,salts thereof, carbonic acid, salts thereof, tartaric acid, saltsthereof, ε-aminocaproic acid, trometamol, and the like. Morespecifically, the salts of phosphoric acid include sodium phosphate,sodium dihydrogen phosphate, disodium hydrogen phosphate, potassiumphosphate, potassium dihydrogen phosphate, dipotassium hydrogenphosphate, and the like; the salts of boric acid include borax, sodiumborate, potassium borate, and the like; the salts of citric acid includesodium citrate, disodium citrate, trisodium citrate, and the like; thesalts of acetic acid include sodium acetate, potassium acetate, and thelike; the salts of carbonic acid include sodium carbonate, sodiumhydrogen carbonate, and the like; the salts of tartaric acid includesodium tartrate, potassium tartrate, and the like. Especially, boricacid, salts thereof, citric acid, and salts thereof are preferable.

When a buffering agent is blended in the therapeutic agent of thepresent invention, the content of the buffering agent can be adjusted,as appropriate, according to the type of the buffering agent and thelike, and is preferably 0.001 to 10% (w/v), more preferably 0.01 to 5%(w/v), further preferably 0.1 to 3% (w/v), and most preferably 0.2 to 2%(w/v).

In the therapeutic agent of the present invention, a tonicity adjustingagent usable as an additive for pharmaceuticals can be blended, asappropriate.

Examples of the tonicity adjusting agent include ionic tonicityadjusting agents, nonionic tonicity adjusting agents, and the like.

The ionic tonicity adjusting agents include sodium chloride, potassiumchloride, calcium chloride, magnesium chloride, and the like. Thenonionic tonicity adjusting agents include glycerin, propylene glycol,sorbitol, mannitol, and the like. When a tonicity adjusting agent isblended in the therapeutic agent of the present invention, the contentof tonicity adjusting agent can be adjusted, as appropriate, accordingto the type of the tonicity adjusting agent and the like, and ispreferably 0.01 to 10% (w/v), more preferably 0.02 to 7% (w/v), furtherpreferably 0.1 to 5% (w/v), particularly preferably 0.5 to 4% (w/v), andmost preferably 0.8 to 3% (w/v).

In the therapeutic agent of the present invention, a stabilizer usableas an additive for pharmaceuticals can be blended, as appropriate.

Examples of the stabilizer include edetic acid, monosodium edetate,disodium edetate, tetrasodium edetate, sodium citrate, and the like, anddisodium edetate is particularly preferable. The sodium edetates may behydrates. When a stabilizer is blended in the therapeutic agent of thepresent invention, the content of the stabilizer can be adjusted, asappropriate, according to the type of the stabilizer and the like, andis preferably 0.001 to 1% (w/v), more preferably 0.005 to 0.5% (w/v),and most preferably 0.01 to 0.1% (w/v).

In the therapeutic agent of the present invention, an antiseptic agentusable as an additive for pharmaceuticals can be blended, asappropriate.

Examples of the antiseptic agents include benzalkonium chloride,benzalkonium bromide, benzethonium chloride, sorbic acid, potassiumsorbate, methyl paraoxybenzoate, propyl paraoxybenzoate, chlorobutanol,and the like. When an antiseptic agent is blended in the therapeuticagent of the present invention, the content of the antiseptic agent canbe adjusted, as appropriate, according to the type of the antisepticagent and the like, and is preferably 0.0001 to 1% (w/v), morepreferably 0.0005 to 0.1% (w/v), further preferably 0.001 to 0.05%(w/v), and most preferably 0.005 to 0.010% (w/v).

In the therapeutic agent of the present invention, an antioxidant usableas an additive for pharmaceuticals can be blended, as appropriate.

Examples of the antioxidant include ascorbic acid, tocopherols,dibutylhydroxytoluene, butylhydroxyanisole, sodium erythorbate, propylgallate, sodium sulfite, and the like. When an antioxidant is blended inthe therapeutic agent of the present invention, the content of theantioxidant can be adjusted, as appropriate, according to the type ofthe antioxidant and the like, and is preferably 0.0001 to 1% (w/v), morepreferably 0.0005 to 0.1% (w/v), and most preferably 0.001 to 0.05%(w/v).

In the therapeutic agent of the present invention, a high-molecularweight polymer usable as an additive for pharmaceuticals can be blended,as appropriate.

Examples of the high-molecular weight polymer include methyl cellulose,ethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose,hydroxypropyl cellulose, hydroxyethyl methyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, carboxy methyl cellulosesodium salt, hydroxypropyl methyl cellulose acetate succinate,hydroxypropyl methyl cellulose phthalate, carboxymethyl ethyl cellulose,cellulose acetate phthalate, polyvinylpyrrolidone, polyvinyl alcohol,carboxyvinyl polymer, polyethylene glycol, and the like.

When a high-molecular weight polymer is blended in the therapeutic agentof the present invention, the content of the high-molecular weightpolymer can be adjusted, as appropriate, according to the type of thehigh-molecular weight polymer and the like, and is preferably 0.001 to5% (w/v), more preferably 0.01 to 1% (w/v), and most preferably 0.1 to0.5% (w/v).

The pH of the therapeutic agent of the present invention is preferably4.0 to 8.0, more preferably 4.5 to 7.5, particularly preferably 5.0 to7.0, and most preferably 5.5 to 6.5. To the therapeutic agent of thepresent invention, a pH adjusting agent for adjusting the pH may beadded such as hydrochloric acid, phosphoric acid, citric acid, aceticacid, sodium hydroxide, potassium hydroxide, or the like.

The therapeutic agent of the present invention can be stored incontainers produced from various materials. For example, a containermade of polyethylene, polypropylene, or the like can be used. Thetherapeutic agent of the present invention is preferably stored in apolyethylene container from the viewpoints of the ease of instillation(hardness of the container), the stability of the present compound, andthe like.

The dosage form of the therapeutic agent of the present invention is notparticularly limited, as long as the dosage form is usable forpharmaceuticals. Specifically, the dosage form may be an eye drop, anophthalmic injection, an ophthalmic ointment, or the like, and isparticularly preferably an eye drop. These dosage forms of these drugscan be produced according to ordinary methods in the technical field. Inaddition, a solvent or dispersion medium used when the therapeutic agentof the present invention is a liquid agent is preferably water.

The therapeutic agent of the present invention may contain or may beused in combination with one or more, preferably 1 to 3, and morepreferably 1 or 2 prophylactic and/or therapeutic agents for glaucoma orocular hypertension other than the present compound. The otherprophylactic and/or therapeutic agents for glaucoma or ocularhypertension are not particularly limited. Specifically, the otherprophylactic and/or therapeutic agents are preferably therapeutic agentsfor glaucoma and the like which are commercially available or underdevelopment, more preferably commercially available therapeutic agentsfor glaucoma and the like, and particularly preferably commerciallyavailable therapeutic agents for glaucoma and the like which havedifferent mechanisms of action from that of the present compound. Morespecifically, the other prophylactic and/or therapeutic agents includenonselective sympathomimetics, α₂ receptor agonists, α₁ receptorblockers, β receptor blockers, parasympathomimetics, carbonic anhydraseinhibitors, prostaglandins, Rho kinase inhibitors, and the like.

A specific example of the nonselective sympathomimetics is dipivefrine.Specific examples of the α₂ receptor agonists include brimonidine andapraclonidine. A specific example of the α₁ receptor blocker isbunazosin. Specific examples of the β receptor blockers include timolol,befunolol, carteolol, nipradilol, betaxolol, levobunolol, andmetipranolol. A specific example of the parasympathomimetics ispilocarpine. Specific examples of the carbonic anhydrase inhibitorsinclude dorzolamide, brinzolamide, and acetazolamide. Specific examplesof the prostaglandins include latanoprost, isopropyl unoprostone,bimatoprost, and travoprost. A specific example of the Rho kinaseinhibitors is ripasudil.

In an embodiment, the therapeutic agent of the present invention doesnot contain any other prophylactic and/or therapeutic agent for glaucomaor ocular hypertension than isopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetateor a salt thereof.

In an embodiment, the therapeutic agent of the present invention is notused in combination with any other prophylactic and/or therapeutic agentfor glaucoma or ocular hypertension than isopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetateor a salt thereof.

The therapeutic agent of the present invention can be administeredorally or parenterally. No special technique is required to preparepharmaceutical preparations of the therapeutic agent, and thepharmaceutical preparations can be prepared by using commonly usedtechniques. The dosage forms for the administration include eye drops,ophthalmic ointments, injections, tablets, capsules, granules, powders,and the like, and eye drops are preferable.

The usage of the therapeutic agent of the present invention is notparticularly limited, as long as the usage is enough to achieve adesired medicinal effect. A suitable usage can be selected, asappropriate, according to symptoms of the disease, the age and bodyweight of the patient, the dosage form of the agent, and the like.Specifically, 1 to 5 drops, preferably 1 to 3 drops, more preferably 1to 2 drops, and particularly preferably 1 drop of the therapeutic agentof the present invention can be instilled 1 to 4 times a day, preferably1 to 3 times a day, more preferably 1 to 2 times a day, and particularlypreferably once a day, every day to every week. It is preferable toinstill one drop of the therapeutic agent of the present invention oncea day, every day. Here, 1 drop is generally approximately 0.01 toapproximately 0.1 mL, preferably approximately 0.015 to approximately0.07 mL, more preferably approximately 0.02 to approximately 0.05 mL,and particularly preferably approximately 0.03 mL.

The therapeutic agent of the present invention is a prophylactic and/ortherapeutic agent for a disease involving a greatly elevated intraocularpressure, and is a pharmaceutical preparation used to rapidly reduce orlower the intraocular pressure.

In the present invention, the “disease involving a greatly elevatedintraocular pressure” refers to a disease with an intraocular pressurein a range of, for example, from 25 to 100 mmHg, preferably from 25 to80 mmHg, more preferably from 30 to 80 mmHg, and further preferably from40 to 80 mmHg. For such a disease, it is necessary to rapidly lower theintraocular pressure.

The “greatly elevated intraocular pressure” which has to be treated orprevented by the present invention includes not only the so-called acuteocular hypertension state as in the case where the intraocular pressureis rapidly elevated to the above-described high intraocular pressurerange in several weeks, several days, or several hours, but also theso-called chronic ocular hypertension state where the above-describedgreatly elevated intraocular pressure is reached over a long period ofseveral months or several years.

Here, the phrase “rapidly reduce the intraocular pressure” or “rapidlylower the intraocular pressure” means that the intraocular pressure isreduced or lowered to a normal level, for example, in a range from 10 to25 mmHg and preferably in a range from 10 to 20 mmHg within, forexample, 24 hours, preferably 12 hours, more preferably 6 hours, furtherpreferably 4 hours, and especially preferably 2 hours. Morespecifically, it is suitable to achieve a reduction in intraocularpressure of −1 to −90 mmHg, preferably −5 to −80 mmHg, more preferably−7 to −70 mmHg, further preferably −10 to −70 mmHg, and most preferably−10 to −60 mmHg, for example, within 6 hours, or it is suitable toachieve a reduction in intraocular pressure of −1 to −90 mmHg,preferably −5 to −80 mmHg, more preferably −7 to −70 mmHg, furtherpreferably −10 to −70 mmHg, and most preferably −10 to −60 mmHg, forexample, within 2 hours. Here, regarding the negative values, forexample, a negative value of “−10 mmHg” means that the intraocularpressure is reduced by 10 mmHg from that before treatment.

In the present invention, examples of the “disease involving a greatlyelevated intraocular pressure” include acute primary angle closure,primary angle closure glaucoma, secondary angle closure glaucoma, andacute intraocular pressure elevation such as that caused by inflammationsuch as uveitis.

Patients with the above-described disease which has to be preventedand/or treated include humans and non-human animals, and, especially,humans and non-human mammals.

EXAMPLES

Hereinafter, Formulation Examples and results of a pharmacological testare shown; however, these are provided for better understanding of thepresent invention, and do not limit the scope of the present invention.

FORMULATION EXAMPLES

Representative Formulation Examples of the therapeutic agent of thepresent invention are shown below. Note that, in the followingFormulation Examples, the blended amount of each component is an amountin 100 mL of the pharmaceutical preparation. In addition, the presentcompound A means isopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate.

Formulation Example 1

Eye drop (in 100 mL) the present compound A 0.002 g  boric acid 0.2 gglycerin 2.0 g polysorbate 80 0.5 g disodium edetate 0.05 g benzalkonium chloride 0.005 g  dilute hydrochloric acid quantum sufficitsodium hydroxide quantum sufficit purified water quantum sufficit

Formulation Example 2

Eye drop (in 100 mL) the present compound A 0.002 g  sodium dihydrogenphosphate 0.2 g glycerin 2.0 g vitamin E TPGS 0.8 g disodium edetate0.05 g  benzalkonium chloride 0.005 g  dilute hydrochloric acid quantumsufficit sodium hydroxide quantum sufficit purified water quantumsufficit

Formulation Example 3

Eye drop (in 100 mL) the present compound A 0.002 g  trisodium citrate0.2 g glycerin 2.0 g polyoxyethylene hardened castor oil 60 0.3 gdisodium edetate 0.05 g  benzalkonium chloride 0.005 g  dilutehydrochloric acid quantum sufficit sodium hydroxide quantum sufficitpurified water quantum sufficit

Note that, it is possible to obtain a desired agent by adjusting thetypes and/or the blended amounts of the present compound A and/or theadditives in any of the above-described Formulation Examples 1 to 3, asappropriate.

[Pharmacological Test]

To investigate the usefulness of the present compound A, an intraocularpressure-lowering effect of the present compound A was tested inexperimental animals (ocular hypertensive monkeys). Regarding testsolutions, a reference solution not containing the present compound Awas used as a control, a solution containing the present compound A wasprepared as Example 1 of the invention of the present application, and alatanoprost eye drop was prepared as Comparative Example 1, as shownbelow.

(Preparation of Test Solutions) (1) Preparation of Reference Solution

To 1.7 g of polyoxyl 35 castor oil, 10 mL of a 0.5% (w/v) disodiumedetate/10% (w/v) glycerin solution, 1 mL of a 1% (w/v) benzalkoniumchloride solution, 30 mL of purified water, and 50 mL of a 2% (w/v)boric acid/0.2% (w/v) sorbic acid solution were added and dissolvedtherein. After dissolution was achieved, the pH of the pharmaceuticalpreparation was adjusted to about 6.5 by adding a suitable amount of asodium hydroxide solution, and the total volume was adjusted to 100 mLby adding a suitable amount of purified water. Thus, a referencesolution serving as a control was prepared.

(2) Preparation of Solution of the Present Compound A (Example 1)

To 2.55 g of polyoxyl 35 castor oil, 0.015 g of the present compound A,15 mL of a 0.5% (w/v) disodium edetate/10% (w/v) glycerin solution, 1.5mL of a 1% (w/v) benzalkonium chloride solution, 45 mL of purifiedwater, and 75 mL of a 2% (w/v) boric acid/0.2% (w/v) sorbic acidsolution were added and dissolved therein. After dissolution wasachieved, the pH of the pharmaceutical preparation was adjusted to about6.5 by adding a suitable amount of a sodium hydroxide solution, and thenthe total volume was adjusted to 150 mL by adding a suitable amount ofpurified water. Thus, a 0.01 w/v % solution of the present compound Awas prepared (Example 1).

(3) Latanoprost Eye Drop (Comparative Example 1)

A commercially available latanoprost eye drop (Trade Name: Xalatan® eyedrop 0.005% (w/v), instillation amount: 20 μL) was used.

(Preparation of Experimental Animals)

Laser-induced ocular hypertensive monkeys (Macaca fascicularis) (sex:male, three groups each consisting of 11 monkeys were prepared in total)were prepared according to the article of Gaasterland and Kupfer(Gaasterland D and Kupfer C., Invest Ophthalmol., 1974, June; 13(6):455-7).

(Testing Method)

(1) For local anesthesia, one drop of a 0.4% oxybuprocaine hydrochlorideeye drop (Trade Name: Benoxil® solution 0.4%) was instilled to an eye ofeach of the experimental animals.

(2) The intraocular pressure was measured immediately beforeinstillation of one of the test solutions (the above-described control,Example 1, and Comparative Example 1), and employed as the initialintraocular pressure.

(3) To the one eye of each of the experimental animals, 20 μL of one ofthe test solutions was instilled (the other eye was not treated).

(4) After 2 hours, 4 hours, and 6 hours had passed from the instillationof the test solution, one drop of the 0.4% oxybuprocaine hydrochlorideeye drop was instilled for local anesthesia to the eye whose intraocularpressure was to be measured, and then the intraocular pressure wasmeasured. In addition, the intraocular pressure was measured threetimes, and the average value was shown in the results.

Note that this test on the three groups was carried out as athree-group, three-period complete-crossover test in which three typesof the test using the control, Example 1, and Comparative Example 1 wereconducted on each of the groups three times in differed periods (inthree periods).

(Results and Discussion) Table 1 shows the average intraocular pressurereduction (relative to the initial intraocular pressure) of each of thetreated groups at 2 hours, 4 hours, and 6 hours after theadministration.

TABLE 1 Average intraocular pressure reduction (vs initial intraocularpressure) (mmHg) 2 hours after 4 hours after 6 hours after Treated groupinstillation instillation instillation Control group −0.5 −1.0 −1.6Example 1- −16.2 −19.3 −19.7 treated group Comparative −7.4 −8.9 −9.3Example 1- treated group * In Table 1, the “negative sign (−)” has sucha meaning that, for example, in the case of −1.0, the intraocularpressure was reduced by 1.0 from the initial intraocular pressure.

As is apparent from Table 1, the intraocular pressure-lowering activityof the present compound A of Example 1 was larger than that in thelatanoprost-treated group of Comparative Example 1, and the presentcompound A of Example 1 exhibited an excellent intraocularpressure-lowering activity no later than 2 hours after theadministration.

From the above-described results, it was found that the present compoundA rapidly provided an excellent intraocular pressure-lowering effectafter the administration in the test on the ocular hypertensive monkeys.

1. A prophylactic and/or therapeutic agent for a disease involving agreatly elevated intraocular pressure, comprising isopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetateor a salt thereof.
 2. The prophylactic and/or therapeutic agentaccording to claim 1, wherein the disease involving a greatly elevatedintraocular pressure is acute primary angle closure, primary angleclosure glaucoma, secondary angle closure glaucoma, or acute intraocularpressure elevation.
 3. The prophylactic and/or therapeutic agentaccording to claim 1, comprising 0.001 to 0.03% (w/v) of the isopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetateor the salt thereof.
 4. The prophylactic and/or therapeutic agentaccording to claim 1, which does not comprise any other prophylacticand/or therapeutic agent for glaucoma or ocular hypertension thanisopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetateor a salt thereof.
 5. An eye drop, comprising the prophylactic and/ortherapeutic agent according to claim
 1. 6. Isopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetateor a salt thereof for the use of preventing and/or treating a diseaseinvolving a greatly elevated intraocular pressure.
 7. Isopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetateor a salt thereof according to claim 6, wherein the disease involving agreatly elevated intraocular pressure is acute primary angle closure,primary angle closure glaucoma, secondary angle closure glaucoma, oracute intraocular pressure elevation.
 8. An eye drop, comprisingisopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetateor a salt thereof according to claim
 6. 9.-13. (canceled)
 14. A methodfor preventing and/or treating a disease involving a greatly elevatedintraocular pressure, comprising administering isopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetateor a salt thereof to patients with said disease which has to beprevented and/or treated.
 15. The method according to claim 14, whereinthe disease involving a greatly elevated intraocular pressure is acuteprimary angle closure, primary angle closure glaucoma, secondary angleclosure glaucoma, or acute intraocular pressure elevation.
 16. Themethod according to claim 14, wherein the administration amount of theisopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetateor the salt thereof is 0.001 to 0.03% (w/v).
 17. The method according toclaim 14, wherein any other prophylactic and/or therapeutic agent forglaucoma or ocular hypertension than isopropyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetateor a salt thereof is not administered.
 18. The method according to claim14, wherein the administration is instillation.